November 30, 2007
Brittney-Shea Herbert, Ph.D.,
Assistant Professor, Department of Medical & Molecular Genetics,
Indiana University School of Medicine,
Indianapolis, Indiana, recently presented the Pathology grand rounds lecture for faculty, residents and staff.
Dr. Herbert's topic, "Mechanisms of Action of Telomerase Template Antagonists in Breast Cancer:
Insights into Rational Combination with Chemotherapy," is highlighted in the following educational objectives:
- Describe different methods of targeting telomerase and current status of clinical trials and use.
- Describe current research in the consequences of telomerase inhibition in breast cancer cells.
- Explain how understanding the mechanisms of telomerase inhibitors can result in developing rational combinational therapy for cancer.
For more information, visit the School of Medicine, Indiana University web site. |
ABSTRACT
Telomeres are repetitive (TTAGGG)n DNA sequences found at the end of chromosomes that protect the ends from fusions and recognition as damaged DNA. Telomerase activity, which maintains telomeres, can be detected in 85-90% of human tumors, but not in most normal tissue. It has therefore been hypothesized that telomerase can be a molecular target for cancer therapy. The telomerase complex itself provides many avenues for molecular targeting. Our laboratory has focused on analyzing thio-phosphoramidate oligonucleotides that target the hTERC, the RNA component of telomerase containing the template region for the catalytic subunit of telomerase. Lipid modification of this telomerase template antagonist (GRN163L, Geron Corporation) results in the potent inhibition of telomerase activity without the use of transfection reagents. Progressive telomere shortening, leading to subsequent growth arrest or cell death, occurs with continuous telomerase inhibition indicating that GRN163L can act as a bona fide telomerase inhibitor. In vivo animal studies showed that the GRN163L had a rapid effect on inhibiting the number of breast cancer metastases and primary breast tumor growth, before the predicted time for the observation of critically short telomeres. To test for novel, potentially telomere-independent mechanisms of GRN163L, cancer cells treated with telomerase inhibitors prior to adherence to culture dishes results in loss of adherence capability, altered morphology, and reduced growth rates. As GRN163L is currently in Phase I/II clinical trials, investigations into its mechanisms can provide insights into developing rational combinations with other forms of chemotherapy, such as DNA damaging agents or taxanes, as well as radiation therapy.
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